The effect of renin-angiotensin-aldosterone system inhibitors on continuous and binary kidney outcomes in subgroups of patients with diabetes: a meta-analysis of randomized clinical trials.

INTRODUCTION: Diabetic nephropathy is the leading cause of kidney failure. Clinical practice guidelines recommend prescribing renin-angiotensin aldosterone system inhibitors (RAASi) to prevent diabetic nephropathy at any stage. We conducted this systematic review and meta-analysis to compare the effects of RAASi with placebo and other antihypertensive agents in adults with diabetes on continuous and binary kidney outcomes to provide a comprehensive review of the class effect of RAASi on several subgroups. METHODS: A systematic electronic search to identify randomized clinical trials of a duration of ≥ 12 months that recruited ≥ 50 adult participants with type 1 or 2 diabetes with any stage of chronic kidney disease and proteinuria was conducted in MEDLINE, CINAHL, EMBASE, and Cochrane library with no language restriction. Studies were screened against the inclusion and exclusion criteria by two reviewers independently. RESULTS: In this meta-analysis, evidence was drawn from 26,551 patients with diabetes from 46 studies. Our analysis shows that RAASi were better than placebo in reducing SrCr (the raw mean difference [RMD] = -13.4 µmol/L; 95%CI: -16.78; -10.01) and albuminuria levels (standardized mean difference [SMD] = -1; 95%CI: -1.57, -0.44, I2 = 96%). When compared to other active treatments, RAASi did not reduce SrCr (RMD = 0.03 µmol/L; 95%CI: -6.4, 6.10, I2 = 76%), caused a non-significant reduction of GFR levels (RMD = -1.21 mL/min; 95%CI: -4.52, 2.09, I2 = 86%), and resulted in modest reduction of albuminuria levels (SMD = -0.55; 95%CI: -0.95, -0.16, I2 = 90%). RAASi were superior to placebo in reducing the risks of kidney failure (OR = 0.74; 95%CI: 0.56, 0.97) and doubling of serum creatinine levels (SrCr; OR = 0.71; 95%CI: 0.55, 0.91), but not in promoting the regression of albuminuria (OR = 3.00; 95%CI: 0.96, 9.37). RAASi, however, were not superior to other antihypertensives in reducing the risks of these outcomes. Patients with type 2 diabetes, macroalbuminuria and longer duration of diabetes had less risk of developing kidney failure in placebo-controlled trials, while longer duration of diabetes, normal kidney function, and hypertension increased the probability of achieving regression of albuminuria in active-controlled trials. CONCLUSION: While our findings revealed the non-superiority of RAASi over other antihypertensives and portrayed a class effect on several subgroups of study participants, it raised a challenging question on whether RAASi deserve their place as first-line therapy in managing diabetic nephropathy.

Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.

BACKGROUND: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. OBJECTIVE: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. METHODS: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. RESULTS: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential TH2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of TH17-related (IL-17A/F and IL-36A/IL-36G), TH1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. CONCLUSION: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.